Hepatocyte transplantation holds great promise as a minimally invasive alternative to organ transplantation to treat life-threatening liver disease. Engrafted hepatocytes can dramatically affect the natural history of liver diseases by amplifying the function of a partially defective liver. Limitations to the application of hepatocyte transplantation include the lack of clinically relevant animal models of acute liver failure that accurately predict the efficacy of new therapies, the lack of an abundant source of hepatocytes, and limited evidence of the longterm engraftment that would be needed to treat liver-based metabolic disorders. We have focused on the use of xenogeneic hepatocytes to overcome the limited availability of human livers, and, at this point, our overarching goal is to refine our approach to allow hepatocyte transplantation to be used more successfully in the clinic and to identify and manage the complications that might be caused by such transplants. We have shown that porcine hepatocytes engraft and function for a period of many months in non-human primates using conventional immune suppression to control rejection. Because there were no well-established models of liver disease in primates at the time, our studies were not able to establish the extent to which hepatocyte xenografts would restore hepatic function in human disease. We have now established a reproducible, clinically-relevant model of acute hepatic failure in cynomolgus monkeys. In addition, we have examined radiation therapy-based liver repopulation strategies for both their efficacy in enhancing long-term donor hepatocyte engraftment and for their effectiveness in rodents in correcting liver-based metabolic disorders, and propose to examine the safety and long-term effectiveness of preparative radiation therapy in augmenting engraftment and partial replacement of the host liver by donor hepatocytes in primates. We hypothesize that porcine hepatocyte transplantation can reverse hepatic failure, and that preparative hepatic radiation-based strategies can dramatically improve the long-term efficacy of hepatocyte transplantation for liver-based metabolic disorders with low risk to patients. Studies in primates will allow us to assess the extent to which 1) a clinical porcine hepatocyte transplantation program can reverse hepatic failure in patients with acute liver failure, 2) liver-directed radiation therapy can safely lead to long-term partial replacement of host hepatocytes by transplanted cells to the degree required for correction of liver-based metabolic disorders in children, 3) the immune response to hepatocyte xenografts is affected by a change in the percentage of the liver replaced, and 4) the immunologic consequences of producing porcine proteins in a primate transplant recipient.